1,4-dihydropyridine-threonine compounds with cardiovascular activity

ABSTRACT

Cardioactive dihydropyridines of the formula  &lt;IMAGE&gt;  in which Y is &lt;IMAGE&gt;  A is H or CH3, B is -NH, -NH-CO-, -NH-CS-, -NH-COO-, -NH-SO2-or -NH-CO-NH- or -NH-CS-NH-, and R13 and R14 each independently is H or an organic radical, and salts thereof. The Y can be hydrolyzed off. The other radicals on the dihydropyridine moiety can also be varied.

The present invention relates to new dihydropyridine derivatives andprocesses for their preparation via new intermediates in their use inthe medical field.

It has already been disclosed that dihydropyridinecarboxylic acids canbe prepared from the corresponding dihydropyridinecarboxylic acidβ-cyanoethyl esters cf. DOS (German Published Specification) No.3,929,545.

The invention relates to dihydropyridine derivatives of the formula (I)##STR3## in which R¹ stands for straight-chain or branched alkyl havingup to 6 carbon atoms which is optionally substituted by halogen,hydroxyl, C₁ -C₈ -alkoxy, carboxyl, C₁ -C₈ -alkoxycarbonyl or phenyl, or

stands for cycloalkyl having 3 to 6 carbon atoms, or

stands for aryl having 6 to 10 carbon atoms which is monosubstituted,disubstituted or trisubstituted by identical or different nitro, cyano,C₁ -C₆ -halogenoalkyl, halogen, C₁ -C₆ -alkyl or C₁ -C₆ -alkoxycarbonyl,or by C₁ -C₆ -halogenoalkoxy, C₁ -C₄ -halogenoalkylthio, carbamoyl,dialkylcarbamoyl having up to 6 carbon atoms per alkyl group, or C₂ -C₈-alkenyl which can optionally be substituted by C₁ -C₆ -alkoxycarbonyl,or by phenylsulphonyloxy which is optionally substituted by C₁ -C₆-alkyl, C₁ -C₆ -alkoxy, nitro, halogen, cyano, C₁ -C₄ -halogenoalkyl orC₁ -C₄ -halogenoalkoxy, or by C₁ -C₈ -alkylamino or dialkylamino eachhaving up to 6 carbon atoms per alkyl group, or C₁ -C₈ -acylamino, or byC₁ -C₈ -alkoxy or C₁ -C₈ -alkylthio, each of which can optionally besubstituted by cyclohexyl or phenyl which, in turn, can be substitutedby halogen, C₁ -C₆ -alkyl, C₁ -C₆ -alkoxy, nitro, C₁ -C₄ -halogenoalkyl,C₁ -C₂ -alkoxycarbonyl, cyano or C₁ -C₄ -halogenoalkoxy, or

stands for a mono-, bi- or tricyclic, saturated or unsaturatedheterocycle which can contain up to 3 hetero atoms from the group N, Oor S and which can be substituted by C₁ -C₄ -alkylthio,

R² stands for nitro, cyano or halogen, or

stands for straight-chain or branched alkyl having up to 12 C atoms, or

stands for phenyl which can be substituted by nitro, cyano, halogen, C₁-C₆ -alkyl, C₁ -C₆ -alkoxy, C₁ -C₆ -alkylthio, trifluoromethyl,trifluoromethoxy, difluoromethoxy or trifluoromethylthio,

stands for a group of the formula ##STR4## wherein R₅ stands forhydrogen, or

stands for a straight-chain, branched on cyclic, saturated orunsaturated hydrocarbon radical having up to 12 C atoms which can beinterrupted by an oxygen or sulphur atom and which can be substituted byN₃, hydroxyl, nitro, halogen, C₁ -C₆ -acyloxy, carboxyl, C₁ -C₆-alkoxycarbonyl, CN or C₁ -C₈ -acyl, or by phenyl or phenoxy which areoptionally substituted by halogen, C₁ -C₄ -alkyl, C₁ -C₄ -alkoxy or C₁-C₂ -halogenoalkyl, or

stands for a radical ##STR5## stands for a group of the formula ##STR6##wherein R¹⁰ and R¹¹ are identical or different and

stand for hydrogen, for straight-chain or branched alkyl having up to 8carbon atoms and which can be substituted by halogen, hydroxyl, alkoxyhaving up to 6 carbon atoms, carboxyl or alkoxycarbonyl having up to 10carbon atoms, or by phenyl which is optionally substituted bytrifluoromethyl, trifluoromethoxy, alkyl having up to 6 carbon atoms,halogen or alkoxy having up to 6 carbon atoms, or

stand for cycloalkyl having 3 to 8 carbon atoms, or

stand for phenyl which can be substituted by identical or differenthalogen, alkyl having up to 6 carbon atoms, alkoxy having up to 6 carbonatoms, alkylthio having up to 4 carbon atoms, trifluoromethyl,trifluoromethoxy, difluoromethoxy, trifluoromethylthio, amino,alkylamino having up to 8 carbon atoms or dialkylamino in each casehaving up to 8 carbon atoms per alkyl group,

or R¹⁰ and R¹¹, together with the nitrogen atom, form a 5- to 7-memberedsaturated or unsaturated heterocyclic ring which can contain an oxygenatom, a sulphur atom or a nitrogen atom as an additional hetero atomwhich can optionally be substituted by a radical R¹²,

wherein

R¹² stands for hydrogen, a straight-chain or branched, saturated orunsaturated alkyl group having up to 4 carbon atoms which can besubstituted by phenyl which, in turn, is substituted by halogen, alkylhaving up to 4 C atoms, alkoxy having up to 4 C atoms, nitro andhalogenoalkyl having up to 4 C atoms, or stands for phenyl which isoptionally substituted by halogen, cyano, nitro, alkyl having up to 4 Catoms or halogenoalkyl having up to 4 C atoms, and

Z denotes a single bond or a straight-chain or branched alkylene chainhaving up to 10 C atoms, and

R⁶ and R⁷ can be identical or different and

stand for hydrogen or C₁ -C₆ -alkyl, or, together with the oxygen atoms,form a 5-membered ring via an ethylene bridge, and

R⁸ stands for straight-chain or branched alkyl having up to 10 carbonatoms, or

stands for a radical ##STR7## or stands for the group ##STR8## whereinR¹⁰ and R¹¹ have the abovementioned meaning, and

R⁹ stands for straight-chain or branched alkyl having up to 8 carbonatoms, or

stands for phenyl which can be substituted by nitro, cyano, halogen,alkyl having up to 2 carbon atoms, alkoxy having up to 2 carbon atoms,trifluoromethyl, trifluoromethoxy or difluoromethoxy, and

R³ stands for straight-chain, branched or cyclic alkyl having up to 6carbon atoms which is optionally substituted by hydroxyl, cyano, phenyl,halogeno or aminoethoxy, or

stands for cyano, or

R² and R³ jointly form a saturated or unsaturated 5- to 7-membered ringwhich can optionally contain up to 3 identical or different ring membersfrom the group comprising ═CH--, --CH₂ --, O, CO, CS, S or --N═, and

R⁴ stands for straight-chain or branched alkyl or alkenyl having up to12 carbon atoms and which can optionally be substituted by halogen,hydroxyl, C₁ -C₆ -alkoxy, trifluoromethyl, carboxyl, C₁ -C₆-alkoxycarbonyl or phenyl which can be substituted by nitro, halogen, C₁-C₂ -alkyl, C₁ -C₄ -alkoxy, trifluoromethyl or trifluoromethoxy, or

stands for cycloalkyl having 3 to 8 carbon atoms, or

stands for phenyl which can optionally be substituted by nitro, halogen,C₁ -C₂ -alkyl or C₁ -C₄ -alkoxy, and

Y stands for a radical ##STR9## wherein A stands for hydrogen or methyl,

and

B stands for a group of the formula --NH, --NH--CO--, --NH--CS--,--NH--COO--, --NH--SO₂ -- or --NH--CO--NH-- or --NH--CS--NH--,

R¹³ stands for hydrogen, or

stands for straight-chain or branched alkyl having up to 12 carbon atomsand which can be substituted by halogen, hydroxyl, carboxyl, cyano, C₁-C₈ -alkoxycarbonyl, carbonyl, alkylamino or dialkylamino having up to 8carbon atoms, carbamoyl, C₁ -C₆ -alkoxy or phenyl which can besubstituted by nitro, cyano, trifluoromethyl, trifluoromethoxy, halogen,C₁ -C₆ -alkoxy or C₁ -C₂ -alkyl, or

stands for cycloalkyl having 3 to 8 carbon atoms, or

stands for phenyl which can be substituted by halogen, C₁ -C₃ -alkyl, C₁-C₃ -alkoxy, C₁ -C₃ -halogenoalkyl or C₁ -C₃ -halogenoalkoxy,

R¹⁴ stands for hydrogen, or

stands for straight-chain or branched alkyl or alkenyl each having up to12 carbon atoms and which can be substituted by halogen, hydroxyl, C₁-C₈ -alkoxy, nitro, cyano, C₁ -C₈ -alkylthio, carboxyl, C₁ -C₈-alkoxycarbonyl or phenyl which can be substituted by nitro, cyano,trifluoromethyl, trifluoromethoxy, C₁ -C₈ -alkyl, halogen or C₁ -C₈-alkoxy, or

stands for cycloalkyl having 3 to 8 carbon atoms, or

stands for aryl having 6 to 10 carbon atoms which can bemonosubsubstituted to pentasubstituted by identical or different nitro,cyano, halogen, C₁ -C₈ -alkyl, C₁ -C₈ -alkoxy, C₁ -C₈ -alkylthio,carbamoyl or dialkylcarbamoyl in each case having up to 6 carbon atomsper alkyl group, carboxyl, C₁ -C₈ -alkoxycarbonyl, C₁ -C₆-halogenoalkyl, C₁ -C₆ -halogenoalkoxy, C₁ -C₆ -halogenoalkylthio, C₁-C₆ -alkylsulphonyl, C₁ -C₆ -alkylsulphamoyl, amino, C₁ -C₈ -alkylaminoor dialkylamino in each case having up to 8 carbon atoms per alkyl groupor C₁ -C₈ -acylamino, or

stands for a 5- to 7-membered saturated or unsaturated, heterocyclicring which can contain one to three oxygen, sulphur and/or nitrogenatoms as hetero atoms,

and their physiologically acceptable salts.

The compounds according to the invention exist in stereoisomeric formswhich either behave as image and mirror image (enantiomers) or which donot behave as image and mirror image (diastereomers). The inventionrelates both to the antipodes and the racemic forms and also the mixtureof diastereomers. The racemic forms can be resolved, just like thediastereomers, into the stereoisomerically uniform constituents in aknown manner (cf. E. L. Eliel, Stereochemistry of Carbon Compounds,McGraw Hill, 1962).

Physiologically acceptable salts may be salts of the compounds accordingto the invention with inorganic or organic acids or bases. Salts withinorganic acids such as, for example, hydrochloric acid, hydrobromicacid, phosphoric acid or sulphuric acid, or salts with organiccarboxylic or sulphonic acids such as, for example, acetic acid, maleicacid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acidor benzoic acid, or methanesulphonic acid, ethanesulphonic acid,phenylsulphonic acid, toluenesulphonic acid or naphthalenedisulphonicacid and salts with bases such as, for example, sodium hydroxide,potassium hydroxide, barium hydroxide or ammonium salts, or salts withorganic bases such as pyridine or triethylamine are preferred.

Preferred compounds of the general formula (I) are those in which

R¹ stands for straight-chain or branched alkyl having up to 4 carbonatoms which can optionally be substituted by phenyl, C₁ -C₂-alkoxycarbonyl or carboxyl, or

stands for phenyl which can be monosubstituted, disubstituted ortrisubstituted by identical or different nitro, cyano, C₁ -C₄-halogenoalkyl, halogen, C₁ -C₄ -alkyl, C₁ -C₄ -alkoxycarbonyl, C₁ -C₂-halogenoalkoxy, C₁ -C₂ -halogenoalkylthio or C₁ -C₄ -alkoxycarbonyl, orby phenylsulphonyloxy which is optionally substituted by C₁ -C₂ -alkylor halogen, or by C₁ -C₄ -alkoxy or C₁ -C₄ -alkylthio, each of which canbe substituted by cyclohexyl or phenyl which can optionally besubstituted by halogen, C₁ -C₄ -alkyl, C₁ -C₄ -alkoxy, nitro, C₁ -C₄-halogenoalkyl, cyano or C₁ -C₄ -halogenoalkoxy, or

stands for a mono- or bicyclic unsaturated heterocycle which can containup to 3 hetero atoms from the group comprising N, O or S, and which canoptionally be substituted by C₁ -C₃ -alkylthio, and

R² stands for nitro or cyano, or

stands for straight-chain or branched alkyl having up to 6 carbon atoms,or

stands for phenyl which can be substituted by nitro, cyano, halogen, C₁-C₂ -alkyl, C₁ -C₂ -alkoxy or trifluoromethyl, or

stands for a group of the formula ##STR10## wherein R⁵ stands forhydrogen, or

stands for a straight-chain, branched or cyclic, saturated orunsaturated hydrocarbon radical having up to 8 carbon atoms and whichcan be interrupted by an oxygen or sulphur atom and which can besubstituted by hydroxyl, nitro, halogen, C₁ -C₆ -alkoxycarbonyl orcarboxyl, or by phenyl or phenoxy which are optionally substituted byhalogen or C₁ -C₂ -alkyl or C₁ -C₂ -alkoxy, or

stands for a group of the formula ##STR11## wherein R¹⁰ and R¹¹ areidentical or different and

stand for hydrogen, or

stand for straight-chain or branched alkyl having up to 8 carbon atomsand which can be substituted by hydroxyl, alkoxy having up to 4 carbonatoms, carboxyl or alkoxycarbonyl having up to 8 carbon atoms, or byphenyl which is optionally substituted by trifluoromethyl,trifluoromethoxy, alkyl having up to 4 carbon atoms, halogen or alkoxyhaving up to 4 carbon atoms, or

stands for cycloalkyl having 3 to 6 carbon atoms, or

stands for phenyl which can be substituted by halogen, alkyl having upto 4 carbon atoms, alkoxy having up to 4 carbon atoms, alkylthio havingup to 4 carbon atoms, trifluoromethyl, trifluoromethoxy ordifluoromethoxy,

or R¹⁰ and R¹¹, together with the nitrogen atom, form a 5- to 7-memberedsaturated heterocyclic ring which can contain an oxygen atom, a sulphuratom or a nitrogen atom as an additional hetero atom, which can besubstituted by a radical R¹²,

wherein

R¹² stands for hydrogen, an alkyl group having up to 4 carbon atomswhich is optionally substituted by phenyl which, in turn, can besubstituted by halogen, C₁ -C₂ -alkyl, C₁ -C₂ -alkoxy or C₁ -C₂-halegenoalkyl, or

stands for phenyl which can optionally be substituted by halogen, C₁ -C₂-alkyl or C₁ -C₂ -halogenoalkyl,

Z denotes a single bond or a straight-chain or branched alkylene chainhaving up to 8 C atoms, and

R⁸ stands for straight-chain or branched alkyl having up to 6 carbonatoms, or

stands for the group ##STR12## wherein R¹⁰ and R¹¹ have theabovementioned meaning, and

R⁹ stands for straight-chain or branched alkyl having up to 4 carbonatoms, or

stands for phenyl which can be substituted by halogen, C₁ -C₂ -alkyl, C₁-C₂ -alkoxy, trifluoromethyl, trifluoromethoxy or difluoromethoxy, and

R³ stands for straight-chain, branched or cyclic alkyl having up to 6carbon atoms which can be substituted by hydroxyl or aminoethoxy, or

R² and R³ jointly form a saturated or unsaturated 5- to 7-membered ringwhich can optionally contain up to 3 different ring members from thegroup comprising ═CH--, --CH₂ --, O, CO, CS, --N═ or S, and

R⁴ stands for straight-chain or branched alkyl having up to 6 carbonatoms which can be substituted by halogen, hydroxyl, carboxyl or C₁ -C₄-alkoxycarbonyl, or can be substituted by phenyl which, in turn, can besubstituted by halogen, C₁ -C₂ -alkyl, C₁ -C₂ -alkoxy, trifluoromethylor trifluoromethoxy, or

stands for cycloalkyl having 3 to 6 carbon atoms, or

stands for phenyl which can optionally be substituted by halogen, C₁ -C₂-alkyl or C₁ -C₂ -alkoxy and

Y stands for a radical ##STR13## wherein A stands for hydrogen or methyland

B stands for a group of the formula --NH, --NH--CO--, --NH--COO--,--NH--SO₂ -- or --NH--CO--NH-- and

R¹³ stands for hydrogen, or

stands for straight-chain or branched alkyl having up to 8 carbon atomswhich can be substituted by halogen, hydroxyl, C₁ -C₃ -alkoxy,trifluoromethyl, carboxyl, C₁ -C₆ -alkoxycarbonyl or phenyl which, inturn, can be substituted by trifluoromethyl, trifluoromethoxy, halogen,C₁ -C₃ -alkoxy or C₁ -C₂ -alkyl, or

stands for cycloalkyl having 3 to 6 carbon atoms, or

stands for phenyl which can be substituted by halogen, C₁ -C₂ -alkyl orC₁ -C₂ -alkoxy, and

R¹⁴ stands for hydrogen, or

stands for straight-chain or branched alkyl or alkenyl each having up to8 carbon atoms and which can be substituted by halogen, hydroxyl, C₁ -C₄-alkoxy, cyano, C₁ -C₄ -alkylthio, carboxyl, C₁ -C₄ -alkoxycarbonyl orphenyl which, in turn, can be substituted by trifluoromethyl,trifluoromethoxy, C₁ -C₄ -alkyl, halogen or C₁ -C₄ -alkoxy, or

stands for cycloalkyl having 3 to 6 carbon atoms, or

stands for phenyl which can be monosubstituted or disubstituted byidentical or different nitro, cyano, halogen, C₁ -C₄ -alkyl, C₁ -C₄-alkoxy, C₁ -C₄ -alkylthio, carbamoyl, dialkylcarbamoyl having up to 4carbon atoms per alkyl group, carboxyl, C₁ -C₆ -alkoxycarbonyl, C₁ -C₃-halogenoalkyl, C₁ -C₃ -halogenoalkoxy, C₁ -C₃ -halogenoalkylthio, C₁-C₃ -alkylsulphonyl, C₁ -C₃ -alkylsulphamoyl, amino, C₁ -C₄ -alkylaminoor dialkylamino in each case having up to 4 carbon atoms per alkyl groupor C₁ -C₄ -acylamino, or stands for a 5- to 6-membered unsaturatedheterocyclic ring which can contain a nitrogen atom as a hetero atom,

and their salts.

In the case in which R² and R³ jointly form a saturated or unsaturated5- to 7-membered ring which can optionally contain up to 3 differentring members from the group O, ═CH--, --CH₂ --, CO, CS, S, --NR^(3') --or --N═, where R^(3') has the meaning of R³, the radicals shown beloware of particular interest ##STR14##

Particularly preferred compounds of the general formula (I) are those

in which

R¹ stands for straight-chain or branched alkyl having up to 4 carbonatoms, or

stands for cyclopropyl, cyclopentyl or cyclohexyl, or

stands for phenyl which can be monosubstituted or disubstituted byidentical or different nitro, cyano, trifluoromethyl, fluorine,chlorine, methyl, methoxy, trifluoromethoxy, difluoromethoxy orphenylsulphonyloxy which is optionally substituted by methyl, fluorineor chlorine, or by C₁ -C₄ -alkoxy or C₁ -C₄ -alkylthio which can each besubstituted by cyclohexyl or phenyl which, in turn, can be substitutedby methyl, fluorine, chlorine or methoxy, or

stands for pyridyl and

R² stands for nitro, or

for a group of the formula ##STR15## wherein R⁵ stands for hydrogen orC₁ -C₆ -alkyl which can optionally be interrupted by oxygen or sulphurand which can optionally be substituted by hydroxyl, C₁ -C₄-alkoxycarbonyl or carboxyl, or by phenyl or phenoxy which is optionallysubstituted by fluorine, chlorine, methyl or methoxy, or

stands for a group of the formula ##STR16## wherein R¹⁰ and R¹¹ areidentical or different and each

stands for hydrogen, for straight-chain or branched alkyl having up to 6carbon atoms and which can be substituted by fluorine, chlorine,hydroxyl, ethoxy, methoxy, carboxyl or C₁ -C₄ -alkoxycarbonyl, or byphenyl which, in turn, can be substituted by trifluoromethyl,trifluoromethoxy, C₁ -C₂ -alkyl, fluorine, chlorine or C₁ -C₂ -alkoxy,or

stands for cyclopropyl, cyclopentyl or cyclohexyl, or

stands for phenyl which can be substituted by fluorine, chlorine, C₁ -C₂-alkyl, C₁ -C₂ -alkoxy, trifluoromethyl, trifluoromethoxy,difluoromethoxy, trifluoromethylthio, amino or C₁ -C₂ -alkylamino, or

R¹⁰ and R¹¹ together stand for piperidinyl, morpholinyl,methyl-piperazinyl or N-benzylpiperazinyl, and

Z stands for a single bond or a straight-chain or branched alkylenechain having up to 6 C atoms and

R⁸ stands for straight-chain or branched alkyl having up to 4 carbonatoms, or

stands for the group ##STR17## wherein R¹⁰ and R¹¹ have theabovementioned meaning, and

R³ stands for straight-chain, branched or cyclic alkyl having up to 4carbon atoms, or

R² and R³ jointly form a ring of the formula ##STR18## and R⁴ stands forstraight-chain or branched alkyl having up to 4 carbon atoms, or

stands for cyclopropyl, and

Y stands for a radical ##STR19## wherein A stands for hydrogen ormethyl, and

B stands for a group of the formula --NH--, --NH--CO--, --NH--COO--,--NH--SO₂ -- or --NH--CO--NH--, and

R¹³ stands for straight-chain or branched alkyl having up to 6 carbonatoms which can be substituted by hydroxyl, methoxy or phenyl, and

R¹⁴ denotes hydrogen, or

stands for straight-chain or branched alkyl having up to 6 carbon atomsand which can be substituted by hydroxyl or C₁ -C₂ -alkoxycarbonyl, orby phenyl which, in turn, can be substituted by methyl, trifluoromethyl,fluorine or chlorine, or

stands for cyclopropyl, cyclopentyl or cyclohexyl, or

stands for phenyl which can be monosubstituted or disubstituted byidentical or different nitro, cyano, fluorine, chlorine, C₁ -C₂ -alkyl,C₁ -C₄ -alkoxy, C₁ -C₂ -alkylthio, carbamoyl, carboxyl, C₁ -C₄-alkoxycarbonyl, trifluoromethyl, trifluoromethoxy, C₁ -C₂-alkylsulphamoyl or C₁ -C₂ -alkylamino, or

stands for pyridyl,

and their salts.

The compounds according to the invention are new and possess usefulpharmacological properties. They influence the contractility of theheart and may therefore be used for the control of cardiovasculardisorders. Owing to the possibility of preparing pure enantiomers, thedesired pharmacological properties of the compounds can be expressed indifferent directions.

The compounds according to the invention of the general formula (I)##STR20## in which R¹, R², R³, R⁴ and Y have the abovementioned meaning,

are obtained by means of the intermediates of the general formula (II)##STR21## in which R⁴ and Y have the abovementioned meanings,

D stands for oxygen or for the group NH,

D* stands for hydroxy or for the group NH₂ and

E stands for two hydrogens or for the group ═CHR¹ in (IIa) or for onehydrogen in (IIb),

wherein

R¹ has the abovementioned meanings,

by a process in which

[A] aldehydes of the general formula (III) ##STR22## in which R¹ has theabovementioned meaning,

and the compounds of the formula (II) ##STR23## in which R⁴ and Y havethe abovementioned meanings,

D stands for oxygen and

E in this case stands for two hydrogen atoms,

directly or optionally after isolation of the obtained benzylidenederivatives are reacted with aminocrotonic acid derivatives of thegeneral formula (IV) ##STR24## in which R² and R² have theabovementioned meanings,

or by a process in which

[B] aldehydes of the general formula (III) ##STR25## in which R¹ has theabovementioned meaning,

are reacted with compounds of the general formula (V) ##STR26## in whichR² and R³ have the abovementioned meanings,

directly or after isolation of the obtained benzylidene derivatives ofthe general formula (VI) ##STR27## in which R¹, R² and R³ have theabovementioned meanings,

are reacted with compounds of the general formula (II) ##STR28## inwhich R⁴ and Y have the abovementioned meanings,

D stands for NH,

D* stands for NH₂ and

E stands for one or two hydrogen atoms.

Depending on the type of starting materials used, the synthesis variantsfor the compounds according to the invention can be represented by thefollowing equations: ##STR29## Suitable solvents for the processvariants A and B are water and all inert organic solvents which do notchange under the reaction conditions. These preferably include alcoholssuch as methanol, ethanol, propanol, isopropanol, ethers such as diethylether, dioxane, tetrahydrofuran, glycol monomethyl ether or glycoldimethyl ether, or amides such as dimethylformamide, dimethylacetamideor hexamethylphosphoric triamide, or glacial acetic acid, dimethylsulphoxide, acetonitrile or pyridine, and hydrocarbons such as toluene,xylene or benzene.

The reaction temperatures can be varied within a relatively large range.In general, the reaction is carried out between +10° C. and +150° C.,preferably between +20° C. and +100° C., in particular at the boilingpoint of the respective solvent.

The reaction can be carried out at atmospheric pressure, but also atelevated or reduced pressure. In general, the reaction is carried atatmospheric pressure.

When carrying out the process variants A and B according to theinvention, the ratio of the substances participating in the reaction isarbitrary. However, in general the reaction is carried out using molaramounts of the reactants. The isolation and purification of thesubstances according to the invention is preferably carried out in sucha way that the solvent is distilled off in vacuo and the residue, whichmay initially be obtained crystalline only after ice cooling, isrecrystallized from a suitable solvent. In some cases, it may benecessary to purify the compounds according to the invention bychromatography.

The compounds of the general formula (II) are new. OnlyL-(2-benzyloxycarbonyl-2-tert.-butoxy-carbonyl-1-methyl)-ethyl3-oxobutanoate is employed as a protecting group in the synthesis ofamino acids [cf. Bull. Chem. Soc. Jpn. 52 (16), 3111-3112].

The invention therefore also relates to the starting materials of thegeneral formula (II), in which R⁴, Y, D and E have the abovementionedmeanings, with the proviso that Y cannot be tert.-butyl if R⁴ denotesmethyl, D denotes oxygen and E denotes two hydrogen atoms. The newcompounds of the formula (II) can be obtained by various processes. Forexample compounds in which

R⁴ stands for methyl,

D stands for oxygen,

E stands for two hydrogen atoms, and

Y has the abovementioned meaning,

can be prepared by a process in which

[A] compounds of the general formula (VIII)

    HO--Y                                                      (VIII)

in which

Y has the abovementioned meaning,

are reacted with diketene of the general formula (IX) ##STR30##

The compounds of the formula (II) in which

R⁴ and Y have the abovementioned meanings,

D stands for oxygen and

E stands for two hydrogen atoms,

can alternatively be prepared by a process in which

[B] compounds of the formula (VIII) are reacted with compounds of thegeneral formula (X) ##STR31## in which R⁴ has the abovementionedmeaning.

The compounds of the general formula (II) in which

R⁴ and Y have the abovementioned meanings,

D stands for NH, D* stands for NH₂ and

E stands for one or two hydrogen atoms,

are obtained by a process in which

[C] compounds of the general formula (II)

in which

R⁴ and Y have the abovementioned meanings,

D stands for oxygen, and

E stands for one or two hydrogen atoms,

are reacted with ammonia.

[D] Compounds of the general formula (II)

in which

R⁴ and Y have the abovementioned meanings,

D denotes oxygen and

E stands for the group R¹ --CH═,

are obtained by a process in which

compounds of the general formula (III)

in which R¹ has the abovementioned meaning, are reacted with compoundsof the general formula (II) in which

R⁴ and Y have the abovementioned meanings,

D stands for oxygen and

E stands for one or two hydrogen atoms.

The aldehydes of the general formula (III) employed as startingmaterials are known or can be prepared by known methods [DOS (GermanPublished Specification) Nos. 2,165,260; 2,401,665; T. D. Harris, G. P.Roth, J. Org. Chem. 44, 2004 (1979); W. J. Dale, H. E. Hennis, J. Am.Chem. Soc. 78, 2543 (1956); Chem. Abstr. 59, 13929 (1963)].

The enamines of the general formula (IV) employed as starting materialsare known or can be prepared by known methods [DOS (German PublishedSpecification) No. 2,228,377; F. A. Glickman, A. C. Cope, J. Am. Chem.Soc. 67, 1017 (1945)].

The ylidene-β-ketocarboxylic acid derivatives of the general formula(VI) employed as starting materials are known or can be prepared byknown methods [G. Jones "The Knoevenagel Condensation" in OrganicReactions Vol. XV, 204 (1967)].

The starting materials of the formula (VIII) are in some cases known orcan be prepared by known methods [cf. Houben-Weyl, Methoden derorganischen Chemie (Methods of Organic Chemistry), Volume 15, part 1, E.Wunsch, page 46 et seq.].

The compound of the formula (IX) and its reactions are known [cf. R. J.Clemens, Chem. Rev. 88, 241 (1986)].

The compounds of the formula (X) are known in some cases or can beprepared by customary methods [cf. J. Org. Chem. 43, 1087 (1978)].

The compounds of the general formula (I) can exist both as mixtures ofdiastereomers and as pure diastereomers. If pure L- or D-compounds areemployed as starting materials of the formula (VIII), in the end pairsof diastereomers of the formula (I) are obtained from these, which, ifdesired, surprisingly can be easily resolved into the pure diastereomersby known methods such as column chromatography, fractionalcrystallization or Craig partition. [For Craig partition see, forexample, "Verteilungsverfahren im Laboratorium ("Partition Methods inthe Laboratory"), E. Hecker, Verlag Chemie GmbH, Weinheim, Bergstrasse(1955)].

This invention in addition relates to the use of compounds of thegeneral formula (I) for the preparation of dihydropyridinecarboxylicacids of the general formula (XI) ##STR32## in which R¹, R², R³ and R⁴have the abovementioned meaning,

and their use as intermediates to make enantiomers of dihydropyridines,because surprisingly it has been found that the radical Y of thecompounds of the formula (I) can be eliminated exceedingly easilycompared to the customary known dihydropyridine esters. If purediastereomers of the formula (I) are employed, pure enantiomericcarboxylic acids of the formula (XI) are obtained, which can betransformed by usual methods into esters, amides, nitriles, lactonesetc. Hereby the pure enantiomeres of dihydropyridines can be easilyobtained.

PREPARATION EXAMPLES Example 1 (With separation of diastereomeres)

(1R,2S)-[1-Methyl-2-methoxycarbonyl-2-(4-tolyl-sulphamoyl)]-ethyl1,4-dihydro-2,6-dimethyl-3-nitro-4-phenylpyridine-5-carboxylate##STR33##

725 mg (3.8 mmol) of benzylidenenitroacetone are boiled for 3 hours with1.4 g (3.8 mmol) of(1R,2S)-[1-methyl-2-methoxycarbonyl-2-(4-tolylsulphamoyl)]-ethylβ-aminocrotonate in 7 ml of ethanol. The mixture is concentrated and thetwo diastereomers are separated by column chromatography.

0.6 g of a yellow-coloured diastereomer of R_(f) =0.18 and 0.4 g of adiastereomer of R_(f) =0.146 are obtained.

TLC: silica gel aluminium roll, silica gel 60, F 254, layer thickness0.2 mm (Merck)

Mobile phase: methylene chloride/ethyl acetate in the volume ratio 20:1.

Example 2 (With separation of diastereomeres)

Methyl (1R,2S)-[1-methyl-2-methoxycarbonyl-2-(4-tolylsulphamoyl)]-ethyl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate##STR34##

5 g (20 mmol) of methyl 2-(3-nitrobenzylidene)-3-oxo-butyrate are boiledfor 5 hours with 7.4 g (20 mmol) of(1R,2S)-[1-methyl-2-methoxy-2-(4-tolylsulphamoyl)]-ethylβ-aminocrotonate in 40 ml of isopropanol. The mixture is cooled, and thedeposited crystals are filtered off with suction and washed withisopropanol. 4.8 g (39.9% of theory) of a pure diastereomer of meltingpoint: 157°-159° C. are obtained (see Example 4). [α]₅₈₉ ²⁰ =+49.3°(c=1.0:DMF).

Example 3 (1R,2S)-(1-Methyl-2-methoxycarbonyl-2-phenyl-carbamoyl)-ethyl1,4-dihydro-2,6-dimethyl-3-nitro-4-phenyl-pyridine-5-carboxylate##STR35##

0.37 g (1.95 mmol) of benzylidene-nitroacetone are boiled in 4 ml ofethanol for 3 hours with 0.6 g (1.95 mmol) of(1R,2S)-(1-methyl-2-methoxycarbonyl-2-phenyl-carbamoyl)-ethylβ-aminocrotonate. The mixture is concentrated and the mixture ofdiastereomers is purified over a silica gel column using toluene/ethylacetate. 0.7 g of a reddish yellow oil of R_(f) 0.1 are obtained (mobilephase: methylene chloride/ethyl acetate 20:1).

Example 4 (With separation of diastereomeres)

Methyl (1R,2S)-1-methyl-2-methoxy-carbonyl-2-(p-tolylsulphamoyl)-ethyl1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate

3.6 g (29.9% of theory) of the other diastereomer are obtained from themother liquor of the compound from Example 2 as an oil by columnchromatography. R_(f) : 0.38 Mobile phase: toluene/acetone (4:1)

Example 5 (Enantiomere acid)

1,4-Dihydro-2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-5-carboxylicacid ##STR36##

1.22 ml (8.15 mmol) of diaza-bicyclo-undecane are added to 2 g (3.33mmol) of the compound from Example 2 in 18 ml of methanol and themixture is stirred at room temperature for 3 hours. It is concentrated,water is added to the residue from the evaporation and the mixture isrendered acidic with 10% strength hydrochloric acid added dropwise withstirring. The deposited solid product is filtered off with suction,washed with water and then with ether. 1.02 g (88.5% of theory) of acolourless product of melting point 181°-182° C. with decomposition areobtained.

[α]₅₈₉ ²⁰ =-21° (c=0.711, acetone) (exceed of enantiomeres (ee)>99%).

The compounds shown in the table below were obtained analogously toExamples 1 to 4.

      ##STR37##       Example No. R.sup.1 R.sup.2 Y M.p. [°C.] R.sub.f (Mobile     phase)         6      ##STR38##      NO.sub.2      ##STR39##       (*1)0.43/0.49      7     ##STR40##      NO.sub.2      ##STR41##      oil175-178 (*1)0.42      8     ##STR42##      NO.sub.2      ##STR43##      115-118 (*2)0.56      9     ##STR44##      NO.sub.2      ##STR45##      oil (*2)0.46      10     ##STR46##      NO.sub.2      ##STR47##      foam (*2)0.36/0.41      11     ##STR48##      H.sub.3      COOC     ##STR49##      oil (*2)0.2/0.24(*1)0.54/0.59      12     ##STR50##      H.sub.3      COOC     ##STR51##      158-160 (*2)0.38/0.41(*1)0.53/0.59      13     ##STR52##      NO.sub.2      ##STR53##      foam (*2)0.02/0.04(*3)0.31      14     ##STR54##      NO.sub.2      ##STR55##      178 (*4)0.16/0.21      15     ##STR56##      NO.sub.2      ##STR57##      oil (*4)0.16/0.19      16     ##STR58##      NO.sub.2      ##STR59##      oil (*4)0.09      17     ##STR60##      NO.sub.2      ##STR61##      oil (*4) 0.29/0.36      18     ##STR62##      NO.sub.2      ##STR63##      178-182 (*4)0.22/0.92(*1)0.22/0.29      19     ##STR64##      H.sub.3      COOC     ##STR65##      oil (*2)0.24/0.29(*1)0.56/0.62      20     ##STR66##      H.sub.3      COOC     ##STR67##      foam (*2)0.394/0.44(*1)0.54/0.59      21     ##STR68##      H.sub.3      COOC     ##STR69##      oil (*2)(*1)0.07/0.21      22     ##STR70##      H.sub.3      COOC     ##STR71##      oil (*1)0.63/0.66(*2)0.4      23     ##STR72##      NO.sub.2      ##STR73##      199-202 (*1)0.55      24     ##STR74##      H.sub.3      COOC     ##STR75##      oil (*5)0.53/0.59(*1)0.89      25     ##STR76##      H.sub.3      COOC     ##STR77##      oil (*1)0.44(*2)0.18      26     ##STR78##       H.sub.3      COOC     ##STR79##      oil (*1)0.43(*2)0.18/0.23      27     ##STR80##      H.sub.3      COOC     ##STR81##      oil (*1)0.17/0.22(*3)0.27/0.32      28     ##STR82##      H.sub.3      COOC     ##STR83##      oil (*6)0.42/0.46      29     ##STR84##      H.sub.3      COOC     ##STR85##      oil (*6)0.32/0.36      30     ##STR86##      ##STR87##      ##STR88##      oil (*3)0.46/0.32      31     ##STR89##      ##STR90##      ##STR91##      foam (*7)0.44/0.5(*3)0.35/0.4      32     ##STR92##      ##STR93##      ##STR94##      foam (*7)0.59/0.65(*3)0.49/0.55      33     ##STR95##      NO.sub.2      ##STR96##      194-197 (*2)0.45      34     ##STR97##      ##STR98##      ##STR99##      foam (*2)0.02(*3)0.42      35     ##STR100##      NO.sub.2      ##STR101##      foam (*1)0.39      36     ##STR102##      NO.sub.2      ##STR103##      180 (*2)0.55      37     ##STR104##      NO.sub.2      ##STR105##      oil (*1)0.26      38     ##STR106##      H.sub.3      COOC     ##STR107##      157-159 (*1)0.29/0.33(*8)0.39/0.47      39     ##STR108##      H.sub.3      COOC     ##STR109##      foam (*4)0.37/0.41      40     ##STR110##      H.sub.3      COOC     ##STR111##      foam (*1)0.67(*9)0.18      41     ##STR112##      H.sub.3      COOC     ##STR113##      foam (*2)0.76/0.82      42     ##STR114##      ##STR115##      ##STR116##      155-157 (*3)0.58/0.64(*10)0.47/0.52      43     ##STR117##      H.sub.5      C.sub.2HNOC     ##STR118##      118-122 (*2)0.05(*3)0.71      44     ##STR119##      H.sub.5      C.sub.2HNOC     ##STR120##       (*7)0.43/0.5(*3)0.46/0.52      45     ##STR121##      NO.sub.2      ##STR122##      178 (*9) 0.48      46     ##STR123##      NO.sub.2      ##STR124##      186-188 (*2)0.56      47     ##STR125##      ##STR126##      ##STR127##      >270      48     ##STR128##      COOCH.sub.3      ##STR129##      oil (*2)0.130.17      49     ##STR130##      COOCH.sub.3      ##STR131##      oil (*1)0.35      50     ##STR132##      ##STR133##      ##STR134##      oil (*1)0.54      51     ##STR135##      ##STR136##      ##STR137##      oil (*1)0.33      52     ##STR138##      ##STR139##      ##STR140##      oil (*1)0.16      53     ##STR141##      COOCH.sub.2CH.sub.2OCH.sub.3      ##STR142##      oil (*1)0.38/0.42      54     ##STR143##      NO.sub.2      ##STR144##      oil 0.56/0.6     (a = R, S; b = S, R)

Intermediate No. 1(1R,2S)-(2-Benzyloxycarbamoyl-2-methoxycarbonyl-1-methyl)-ethylacetoacetate ##STR145##

(a) Preparation of methyl (2S,3R)-2-amino-3-hydroxybutyrate

109 ml (1.5 mol) of thionyl chloride are added dropwise at 0° C. withstrong cooling to 240 ml of methanol. 60 g (0.5 mol) of L-threonine arethen added and the mixture is stirred at room temperature for 2 days, aclear solution resulting. After concentration, 85 g of a colorless oilare obtained.

(b) Preparation of methyl(2S,3R)-2-benzyloxycarbonylamino-3-hydroxybutyrate

34.1 g (0.201 mol) of methyl (2S,3R)-2-amino-3-hydroxybutyrate are mixedin 300 ml of ethyl acetate with a solution of 40 g of potassiumcarbonate in 200 ml of water. 33 ml (0.215 mol) of 90% strengthbenzyloxy-carbonyl chloride are then added dropwise at 0° C. The mixtureis stirred at 0°-5° C. for 2 hours and separated, and the ethyl acetatephase is washed twice with water, dried and concentrated. Hexane isadded to the crystals obtained and filtered off with suction. 42.2 g(78.6%) of colorless crystals of melting point 96° C. are obtained.

0.2 ml of triethylamine is added to 35 g (0.13 mol) of methyl(2S,3R)-2-benzyloxycarbonylamino-3-hydroxy-butyrate in 75 ml of absolutetoluene. 9.8 ml (0.13 mmol) of diketene, dissolved in 10 ml of absolutetoluene, are added dropwise at 90° C., the temperature being keptbetween 90° C. and 98° C. The mixture is subsequently stirred at 95° C.for 2 hours, cooled, shaken once with water, dried and concentrated.44.3 g (96.6% of theory) of a brown-colored oil are obtained.

Intermediate No. 2(1R,2S)-[1-methyl-2-methoxycarbonyl-2-(4-nitrophenylsulphamoyl)]-ethyl3-imino-acetoacetate or(1R,2S)-[1-methyl-2-methoxycarbonyl-2-(4-nitrophenylsulphamoyl)]-ethylβ-aminocrotonate ##STR146##

200 mg of p-toluenesulphonic acid are added to 39.2 g (97.5 mmol) of(1R,2S)-[1-methyl-2-methoxycarbonyl-2-(4-nitrophenylsulphamoyl)]-ethylacetoacetate in 370 ml of toluene and the mixture is boiled in a waterseparator for 4 hours, ammonia being introduced at the same time. Themixture is cooled, shaken twice with water, dried and concentrated. Thecrystals obtained are stirred with a little ethanol, filtered off withsuction and washed with ethanol and ether. 20.2 g of beige-coloredcrystals of melting point 155°-156° C. are obtained.

Intermediate No. 3(1R,2S)-[1-Methyl-2-methoxycarbonyl-2-(3,5-dinitrophenylcarbamoyl)]-ethyl2-(2-benzyloxybenzylidene)-3-oxo-butyrate ##STR147##

100 g (243.5 mmol) of(1R,2S)-[1-methyl-2-methoxycarbonyl-2-(3,5-dinitrophenylcarbamoyl)]-ethylacetoacetate are stirred in 300 ml of isopropanol with 51.3 g (243.5mmol) of 2-benzyloxybenzaldehyde. A freshly prepared solution of 1.5 mlof piperidine and 0.75 ml of acetic acid in 12 ml of isopropanol isadded to this suspension. The mixture is stirred at 40°-45° C. for 4hours, a non-crystalline magma being formed initially andcrystallization then occurring. The crystals are filtered with suctionand washed with isopropanol and ether. 123.6 g (83.9% of theory) of apale brown product of melting point 143°-146° C. are obtained.

The intermediates shown in the table below were obtained analogously tothe directions for intermediates No. 1 to 3.

    __________________________________________________________________________    Intermediate                                                                  Example                                      M.p.: Configuration              No.    B          R.sup.13         R.sup.14  R.sub.f :                                                                           (*1) (1);                  __________________________________________________________________________                                                       (2)                         ##STR148##                                                                   4      NHCOO      CH.sub.3         C(CH.sub.3).sub.3                                                                       oil, 0.6                                                                            R,S                        5      NHCOO      CH(CH.sub.3).sub.2                                                                             C(CH.sub.3).sub.3                                                                       oil, 0.62                                                                           R,S                        6      NHCOO      CH(CH.sub.3).sub.2                                                                              ##STR149##                                                                             oil, 0.7                                                                            R,S                        7      NHSO.sub.2 CH.sub.3                                                                                        ##STR150##                                                                             85°                                                                          R,S                        8      NHCO       CH(CH.sub.3).sub.2                                                                              ##STR151##                                                                             oil, 0.61                                                                           R,S                        9      NHCO       CH.sub.3                                                                                        ##STR152##                                                                             oil, 0.5                                                                            R,S                        10     NHSO.sub.2 CH.sub.3                                                                                        ##STR153##                                                                             at 78° C.                                                                    R,S                        11     NHCO       CH.sub.3                                                                                        ##STR154##                                                                             at 84° C.                                                                    R,S                        12     NHCOO      CH.sub.3         CH.sub.3  70-72° C.                                                                    R,S                        13     NHSO.sub.2 CH.sub.3         CH.sub.3  oil, 0.29                                                                           R,S                        14     NHCO       CH3              CH.sub.3  oil, 0.31                                                                           R,S                        15     NHSO.sub.2 CH.sub.3                                                                                        ##STR155##                                                                             95-96° C.                                                                    R,S                        16     NHSO.sub.2 CH.sub.3                                                                                        ##STR156##                                                                             105-106° C.                                                                  R,S                        17     NHCO       CH.sub.3                                                                                        ##STR157##                                                                             79-84° C.                                                                    R,S                        18     NHSO.sub.2 CH(CH.sub.3).sub.2                                                                              ##STR158##                                                                             100° C.                                                                      R,S                        19     NHCO       CH(CH.sub.3).sub.2                                                                              ##STR159##                                                                             162-165° C.                                                                  R,S                        20     NHSO.sub. 2                                                                              CH.sub.3                                                                                        ##STR160##                                                                             99-100° C.                                                                   S,R                        21     NHCO       CH.sub.3                                                                                        ##STR161##                                                                             83° C.                                                                       S,R                        22     NHSO.sub.2 CH(CH.sub.3).sub.2                                                                              ##STR162##     R,S                        22a    NHCONH     CH.sub.3                                                                                        ##STR163##     R,S                         ##STR164##                                                                   23     NHCOO      CH.sub.3                                                                                        ##STR165##                                                                             oil, 0.61                                                                           R,S                        24     NHCOO      CH.sub.3         C(CH.sub.3).sub.3                                                                       0.6   R,S                        25     NHSO.sub.2 CH.sub.3                                                                                        ##STR166##                                                                             94-96° C.                                                                    R,S                        26     NHCOO      CH(CH.sub.3).sub.2                                                                              ##STR167##                                                                             oil, 0.69                                                                           R,S                        27     NHCOO      CH(CH.sub.3).sub.2                                                                             C(CH.sub.3).sub.3                                                                       93-95° C.                                                                    R,S                        28     NHCO       CH(CH.sub.3).sub.2                                                                              ##STR168##                                                                             oil, 0.59                                                                           R,S                        29     NHCO       CH.sub.3                                                                                        ##STR169##                                                                             oil, 0.5                                                                            R,S                        30     NHSO.sub.2 CH.sub.3                                                                                        ##STR170##                                                                             114-115° C.                                                                  S,R                        31     NHSO.sub.2 CH.sub.3                                                                                        ##STR171##                                                                             152-155° C.                                                                  R,S                        32     NHCO       CH.sub.3                                                                                        ##STR172##                                                                             102-103° C.                                                                  R,S                        33     NHCOO      CH.sub.3         CH.sub.3  oil, 0.32                                                                           R,S                        34     NHSO.sub.2 CH.sub.3         CH.sub.3  oil, 0.28                                                                           R,S                        35     NHCO       CH.sub.3         CH.sub.3        R,S                        36     NHSO.sub.2 CH.sub.3                                                                                        ##STR173##                                                                             82-86° C.                                                                    R,S                        37     NH SO.sub.2                                                                              CH.sub.3                                                                                        ##STR174##                                                                             120° C.                                                                      R,S                        38     NHCO       CH.sub.3                                                                                        ##STR175##                                                                             161-164° C.                                                                  R,S                        39     NHSO.sub.2 CH(CH.sub.3).sub.2                                                                              ##STR176##                                                                             153-156° C.                                                                  R,S                        40     NHSO.sub.2 CH(CH.sub.3).sub.2                                                                              ##STR177##                                                                             180-182° C.                                                                  R,S                        41     NHCO       CH(CH.sub.3).sub.2                                                                              ##STR178##                                                                             155-159° C.                                                                  R,S                        __________________________________________________________________________    Intermediate                                                                  Example                                      M.p.: Configuration              No.    B          E                R.sup.14  R.sub.f.:                                                                           (1);                       __________________________________________________________________________                                                       (2)                         ##STR179##                                                                   42     NHSO.sub.2                                                                                ##STR180##                                                                                     ##STR181##                                                                             oil, 0.8                                                                            R,S                        43     NHCO                                                                                      ##STR182##                                                                                     ##STR183##                                                                             141° C.                                                                      S,R                        44     NHSO.sub.2                                                                                ##STR184##                                                                                     ##STR185##                                                                             oil   R,S                        45     NHCONH                                                                                    ##STR186##                                                                                     ##STR187##     R,S                        46     NHSO.sub.2                                                                                ##STR188##                                                                                     ##STR189##                                                                             oil, 0 8                                                                            S,R                        __________________________________________________________________________     Explanation of symbols for the tables                                         (*1) Toluene/ethyl acetate 1:1                                                (*2) Methylene chloride/ethyl acetate 9:1                                     (*3) Methylene chloride/ethyl acetate 1:4                                     (*4) Methylene chloride/ethyl acetate 20:1                                    (*5) Chloroform/ethyl acetate 9:1                                             (*6) Toluene/ethyl acetate 2:1                                                (*7) Ethyl acetate                                                            (*8) Toluene/methyl isobutyl ketone 3:1                                       (*9) Toluene/ethyl acetate 4:1                                                (*10) Toluene/ethyl acetate 1:5                                          

It will be understood that the specification and examples areillustrative but not limitative of the present invention and that otherembodiments within the spirit and scope of the invention will suggestthemselves to those skilled in the art.

We claim:
 1. A dihydropyridine compound of the formula ##STR190## inwhich R¹ represents aryl having 6 to 10 carbon atoms which ismonosubstituted, disubstituted or trisubstituted by identical ordifferent nitro, cyano, C₁ -C₆ -halogenoalkyl, halogen, C₁ -C₆ -alkyl orC₁ -C₆ -alkoxycarbonyl, or by C₁ -C₆ halogenoalkoxy, C₁ -C₄-halogenoalkylthio, carbamoyl, dialkyl carbamoyl having up to 6 carbonatoms per alkyl group, or C₂ -C₈ -alkenyl which can optionally besubstituted by C₁ -C₆ -alkoxycarbonyl or by phenylsulphonyloxy which isoptionally substituted by C₁ -C₆ -alkyl, C₁ -C₆ -alkoxy, nitro, halogen,cyano, C₁ -C₄ -halogenoalkyl or C₁ -C₄ -halogenoalkoxy, or by C₁ -C₈-alkyl-amino or dialkylamino each having up to 6 carbon atoms per alkylgroup, or C₁ -C₈ -alkyl-amino or dialkylamino each having up to 6 carbonatoms per alkyl group, or C₁ -C₈ -acylamino, or by C₁ -C₈ -alkoxy or C₁-C₈ -alkylthio, each of which can optionally be substituted bycyclohexyl or phenyl which, in turn, can be substituted by cyclohexyl orphenyl which, in turn, can be substituted by halogen, C₁ -C₆ -alkyl, C₁-C₆ -alkoxy, nitro, C₁ -C₄ -halogenoalkyl, C₁ -C₂ -alkoxycarbonyl, cyanoor C₁ -C₄ -halogenoalkoxy,R² represents a group of the formulaCOO--Z--R⁵ wherein R⁵ represents hydrogen, or represents astraight-chain, branched or cyclic, saturated or unsaturated hydrocarbonradical having up to 12 C atoms which can be interrupted by an oxygen orsulphur atom and which can be substituted by NO₃, hydroxyl, nitro,halogen, C₁ -C₆ -acyloxy, carboxyl, C₁ -C₆ -alkoxycarbonyl, CN or C₁ -C₈-acyl, or by phenyl or phenoxy which are optionally substituted byhalogen, C₁ -C₄ -alkyl, C₁ -C₄ -alkoxy or C₁ -C₂ -halogenoalkyl,Z-denotes a single bond or a straight-chain or branched alkylene chainhaving up to 10 C atoms, R³ represents straight-chain, branched orcyclic alkyl having up to 6 carbon atoms which is optionally substitutedby hydroxyl, cyano, phenyl, halogeno or aminoethoxy, R⁴ representsstraight-chain or branched alkyl or alkenyl having up to 12 carbon atomsand which can optionally be substituted by halogen, hydroxyl, C₁ -C₆-alkoxy, trifluoromethyl, carboxyl, C₁ -C₆ -alkoxycarbonyl or phenylwhich can be substituted by nitro, halogen, C₁ -C₂ -alkyl, C₁ -C₄-alkoxy, trifluoromethyl or trifluoromethoxy, Y represents a radical##STR191## wherein A represents hydrogen or methyl, B represents a groupof the formula--NH, --NH--CO--, --NH--CS--, --NH--COO--, --NH--SO₂ -- or--NH--CO--NH-- or --NH--CS--NH, R¹³ represents for hydrogen, or standsfor straight-chain or branched alkyl having up to 12 carbon atoms andwhich can be substituted by halogen, hydroxyl, carboxy, cyano, C₁ -C₈-alkoxycarbonyl, carbonyl, alkylamino or dialkylamino having up to 8carbon atoms, carbamoyl, C₁ -C₆ -alkoxy or phenyl which can besubstituted by nitro, cyano, trifluoromethyl, trifluoromethoxy, halogen,C₁ -C₆ -alkyl, and R¹⁴ represents hydrogen, or represents straight-chainor branched alkyl or alkenyl each having up to 12 carbon atoms and whichcan be substituted by halogen, hydroxyl, C₁ -C₈ -alkoxy, nitro, cyano,C₁ -C₈ -alkylthio, carboxyl, C₁ -C₈ -alkoxycarbonyl or phenyl which canbe substituted by nitro, cyano, trifluoromethyl, trigluoromethoxy, C₁-C₈ -alkyl, halogen or C₁ -C₈ -alkoxy or represents cycloalkyl having 3to 8 carbon atoms, or represents aryl having 6 to 10 carbon atoms whichcan be monosubstituted to pentasubstituted by identical or differentnitro, cyano, halogen, C₁ -C₈ -alkyl, C₁ -C₈ -alkoxy, C₁ -C₈ -alkylthio,carbamoyl or dialkylcarbamoyl in each case having up to 6 carbon atomsper alkyl group, carboxyl, C₁ -C₈ -alkoxycarbonyl, C₁ -C₆-halogenoalkylthio, C₁ -C₆ -halogenoalkoxy, C₁ -C₆ -halogenoalkylthio,C₁ -C₆ -halogenoalkoxy, C₁ -C₆ -halogenoalkylthio, C₁ -C₆-alkylsulphonyl, C₁ -C₆ -alkylsulphamoyl, amino, C₁ -C₈ -alkylamino ordialkylamino in each case having up to 8 carbon atoms per alkyl group orC₁ -C₈ -acylamino, or a physiologically acceptable salt thereof.
 2. Acompound according to claim 1, wherein such compound is methyl[1-methyl-2-methoxycarbonyl-2-(4-tolyl-sulphamoyl)]-ethyl1,4-dihydro-2,6-dimethyl-4-(2-benzyloxy)-pyridine-3,5-dicarboxylate ofthe formula ##STR192## or a physiologically acceptable salt thereof. 3.A cardioactive composition comprising a cardioactive amount of acompound or salt thereof according to claim 1 and a pharmaceuticallyacceptable diluent.
 4. A unit dose of a composition according to claim 3in the form of a tablet, capsule or ampule.
 5. A method of modifying thecontractility of the heart of a patient in need thereof which comprisesadministering to such patient an amount effective therefor of acardioactive amount of a compound or a salt thereof according toclaim
 1. 6. The method according to claim 5, wherein such compoundismethyl [1-methyl-2-methoxycarbonyl-2-(4-tolylsulphamoyl)]-ethyl1,4-dihydro-2,6-dimethyl-4-(2-benzyloxy)-pyridine-3,5-dicarboxylate,methyl [1-methyl-2-methoxycarbonyl-2-(4-nitrophenylcarbamoyl)]-ethyl1,4-dihydro-2,6-dimethyl-4-(2-benzyloxy)-pyridine-3,5-dicarboxylate, ormethyl [1-methyl-2-methoxycarbonyl-2-(3,5-dinitrophenylcarbanitk)]-ethyl1,4-dihydro-2,6-dimethyl-4-(2-benzyloxy)-pyridine-3,5-dicarboxylate.